Lebeda2008 - BoNT paralysis (3 step model)

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Short description
Lebeda2008 - BoNT paralysis (3 step model)
The onset of paralysis of skeletal muscles induced by BoNT/A at the isolated rat neuromuscular junction is describing in the model. This is the 3-step model described in the paper. This model is the reduced form of the model developed my Simpson 1980; PMID:   6243359  , i.e., it omits three unknown parameters that represents the binding sites for each species of the toxin. The extension to this model, i.e. the 4-step model described in the paper is BIOMD0000000178.

This model is described in the article:

Lebeda FJ, Adler M, Erickson K, Chushak Y.
J Pharmacokinet Pharmacodyn 2008 Jun; 35(3): 251-267

Abstract:

Experimental studies have demonstrated that botulinum neurotoxin serotype A (BoNT/A) causes flaccid paralysis by a multi-step mechanism. Following its binding to specific receptors at peripheral cholinergic nerve endings, BoNT/A is internalized by receptor-mediated endocytosis. Subsequently its zinc-dependent catalytic domain translocates into the neuroplasm where it cleaves a vesicle-docking protein, SNAP-25, to block neurally evoked cholinergic neurotransmission. We tested the hypothesis that mathematical models having a minimal number of reactions and reactants can simulate published data concerning the onset of paralysis of skeletal muscles induced by BoNT/A at the isolated rat neuromuscular junction (NMJ) and in other systems. Experimental data from several laboratories were simulated with two different models that were represented by sets of coupled, first-order differential equations. In this study, the 3-step sequential model developed by Simpson (J Pharmacol Exp Ther 212:16-21,1980) was used to estimate upper limits of the times during which anti-toxins and other impermeable inhibitors of BoNT/A can exert an effect. The experimentally determined binding reaction rate was verified to be consistent with published estimates for the rate constants for BoNT/A binding to and dissociating from its receptors. Because this 3-step model was not designed to reproduce temporal changes in paralysis with different toxin concentrations, a new BoNT/A species and rate (k(S)) were added at the beginning of the reaction sequence to create a 4-step scheme. This unbound initial species is transformed at a rate determined by k(S) to a free species that is capable of binding. By systematically adjusting the values of k(S), the 4-step model simulated the rapid decline in NMJ function (k(S) >or= 0.01), the less rapid onset of paralysis in mice following i.m. injections (k (S) = 0.001), and the slow onset of the therapeutic effects of BoNT/A (k(S) < 0.001) in man. This minimal modeling approach was not only verified by simulating experimental results, it helped to quantitatively define the time available for an inhibitor to have some effect (t(inhib)) and the relation between this time and the rate of paralysis onset. The 4-step model predicted that as the rate of paralysis becomes slower, the estimated upper limits of (t(inhib)) for impermeable inhibitors become longer. More generally, this modeling approach may be useful in studying the kinetics of other toxins or viruses that invade host cells by similar mechanisms, e.g., receptor-mediated endocytosis.

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Format
SBML (L2V4)
Related Publication
  • Onset dynamics of type A botulinum neurotoxin-induced paralysis.
  • Lebeda FJ, Adler M, Erickson K, Chushak Y
  • Journal of pharmacokinetics and pharmacodynamics , 6/ 2008 , Volume 35 , pages: 251-267
  • Integrated Toxicology Division, US Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD 21702-5011, USA. Frank.Lebeda@amedd.army.mil
  • Experimental studies have demonstrated that botulinum neurotoxin serotype A (BoNT/A) causes flaccid paralysis by a multi-step mechanism. Following its binding to specific receptors at peripheral cholinergic nerve endings, BoNT/A is internalized by receptor-mediated endocytosis. Subsequently its zinc-dependent catalytic domain translocates into the neuroplasm where it cleaves a vesicle-docking protein, SNAP-25, to block neurally evoked cholinergic neurotransmission. We tested the hypothesis that mathematical models having a minimal number of reactions and reactants can simulate published data concerning the onset of paralysis of skeletal muscles induced by BoNT/A at the isolated rat neuromuscular junction (NMJ) and in other systems. Experimental data from several laboratories were simulated with two different models that were represented by sets of coupled, first-order differential equations. In this study, the 3-step sequential model developed by Simpson (J Pharmacol Exp Ther 212:16-21,1980) was used to estimate upper limits of the times during which anti-toxins and other impermeable inhibitors of BoNT/A can exert an effect. The experimentally determined binding reaction rate was verified to be consistent with published estimates for the rate constants for BoNT/A binding to and dissociating from its receptors. Because this 3-step model was not designed to reproduce temporal changes in paralysis with different toxin concentrations, a new BoNT/A species and rate (k(S)) were added at the beginning of the reaction sequence to create a 4-step scheme. This unbound initial species is transformed at a rate determined by k(S) to a free species that is capable of binding. By systematically adjusting the values of k(S), the 4-step model simulated the rapid decline in NMJ function (k(S) >or= 0.01), the less rapid onset of paralysis in mice following i.m. injections (k (S) = 0.001), and the slow onset of the therapeutic effects of BoNT/A (k(S) < 0.001) in man. This minimal modeling approach was not only verified by simulating experimental results, it helped to quantitatively define the time available for an inhibitor to have some effect (t(inhib)) and the relation between this time and the rate of paralysis onset. The 4-step model predicted that as the rate of paralysis becomes slower, the estimated upper limits of (t(inhib)) for impermeable inhibitors become longer. More generally, this modeling approach may be useful in studying the kinetics of other toxins or viruses that invade host cells by similar mechanisms, e.g., receptor-mediated endocytosis.
Contributors
Vijayalakshmi Chelliah

Metadata information

is
BioModels Database MODEL1009070000
BioModels Database BIOMD0000000267
isDescribedBy
PubMed 18551355
isDerivedFrom
PubMed 6243359
hasTaxon
Taxonomy Homo sapiens
Taxonomy Mus musculus
Taxonomy Rattus norvegicus
hasProperty
Human Disease Ontology botulism
Curation status
Curated
  • Model originally submitted by : Vijayalakshmi Chelliah
  • Submitted: 07-Sep-2010 15:13:32
  • Last Modified: 18-May-2017 12:13:55
Revisions
  • Version: 2 public model Download this version
    • Submitted on: 18-May-2017 12:13:55
    • Submitted by: Vijayalakshmi Chelliah
    • With comment: Current version of Lebeda2008 - BoNT paralysis (3 step model)
  • Version: 1 public model Download this version
    • Submitted on: 07-Sep-2010 15:13:32
    • Submitted by: Vijayalakshmi Chelliah
    • With comment: Original import of Lebeda2008_BoNT_Paralysis_3stepModel
Curator's comment:
(added: 07 Sep 2010, 15:22:06, updated: 07 Sep 2010, 15:22:06)
Figure 1 of the reference publication has been reproduced. The model was integrated and simulated using Copasi v4.5 31